Brain Cell Senescence: A New Therapeutic Target for the Acute Treatment of Ischemic Stroke

Abstract

Aging is a major risk factor for cerebral infarction. Since cellular senescence is intrinsic to aging, we postulated that stroke-induced cellular senescence might contribute to neural dysfunction. Adult male Wistar rats underwent 60-minute middle cerebral artery occlusion and were grouped according to 3 reperfusion times: 24 hours, 3, and 7 days. The major biomarkers of senescence: 1) accumulation of the lysosomal pigment, lipofuscin; 2) expression of the cell cycle arrest markers p21, p53, and p16INK4a; and 3) expression of the senescence-associated secretory phenotype cytokines interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and interleukin-1β (IL-1β) were investigated in brain samples. Lipofuscin accumulation was scarce at the initial stage of brain damage (24 hours), but progressively increased until it reached massive distribution at 7 days post-ischemia. Lipofuscin granules (aggresomes) were mainly confined to the infarcted areas, that is parietal cortex and adjacent caudate-putamen, which were equally affected. The expression of p21, p53, and p16INK4a, and that of IL-6, TNF-α, and IL-1β, was significantly higher in the ischemic hemisphere than in the non-ischemic hemisphere. These data indicate that brain cell senescence develops during acute ischemic infarction and suggest that the acute treatment of ischemic stroke might be enhanced using senolytic drugs.

Patients with sporadic FTLD exhibit similar increases in lysosomal proteins and storage material as patients with FTD due to GRN mutations

“…Similar increases in neuronal cathepsin D and lysosomal storage material have been observed in degenerated regions of brains from patients with Alzheimer’s disease (AD) [ 21 , 22 ], though these changes are closely associated with AD pathology [ 23 ]. Accumulation of lysosomal storage material has also been observed in models of stroke [ 9 ], excitotoxicity [ 48 ] and traumatic brain injury [ 45 , 47 , 70 ], perhaps indicating a general relationship with neuronal stress or death. In contrast, CatD levels increase in some models of injury and excitotoxicity [ 11 , 13 , 16 ], but decrease in models of hypoxia and stroke [ 61 ] and at early time points after traumatic brain injury [ 74 ].…”

Transcriptomic analysis reveals the potential biological mechanism of AIS and lung adenocarcinoma

“…Numerous neurological diseases, including neurodegenerative conditions like Alzheimer's disease, Parkinson's disease, and stroke, are linked to cellular senescence ( 35 ). Cellular senescence of the cells happens as AIS, which develops and progresses ( 36 ). AIS and neurological damage are impacted by the senescence-associated secretory phenotype (SASP) ( 37 ).…”

Cellular senescence in ischemia/reperfusion injury

“…In addition to the kidney and heart, brain is also prone to suffer from I/R injury. A recent study also showed that neuron senescence served as a pathogenic mechanism for ischemic stroke-induced brain damage [ 99 , 100 ], which might result in glial scar and cerebral fibrosis [ 101 ].…”

“…On the one hand, senescent neurons induced by stroke have a significant increase in the expression of SASP including IL6, TNFα, and CXCL1 [ 99 , 100 , 102 ], which induce cerebral inflammation microenvironment forming and extracellular matrix(ECM) deposition by a pericyte-dependent manner [ 101 ]. On the other hand, in the early stages of cerebral IR injury, glial cells especially astrocytes are activated by pro-inflammatory cytokines generated by senescent neurons [ 101 , 103 , 104 ].…”